The candidate, Dr. Detlef Wencker, Assistant Professor of Medicine, joined the Section of Cardiovascular Medicine and Heart Failurerfransplant Program at Yale University in order to carry on his past research endeavors with the long-term goal of becoming an independent investigator. In extension of his prior work, he has chosen to investigate the basic mechanism of heart failure (CHF) in humans in order to find new treatment modalities that target the cellular origin of the disease. Yale University with its outstanding clinical and basic science research environment combined with a highly effective mentorship by Dr. Stuart Katz places the candidate in a strong position to accomplish this task. This award will allow the candidate to continue his research career development by obtaining a Masters in Public Health in Biostatistics and by consolidating his knowledge of both clinical and basic science. The proposed research seeks to identify the role of apoptosis in decompensating CHF among patients with end-stage dilated cardiomyopathy. Preliminary data suggest that skeletal muscle apoptosis is upregulated during acute CHF exacerbation. Aim 1will investigate the hypothesis that myocyte apoptosis of the skeletal muscle undergoes a dynamic process from stable, compensated CHF to acute cardiac decompensation. The second aim hypothesizes that the dynamics of apoptosis in the skeletal muscle parallels that in the heart. The candidate will monitor the rate of apoptosis, the level of pro-apoptotic inflammatory cytokines and the state of apoptotic regulators in skeletal and cardiac muscle specimens of CHF patients longitudinally at times of compensation and times of acute CHF exacerbation. Specific aim 3 will examine if treatment with erythropoietin, a glycoprotein with potent anti-apoptotic properties, of patients with moderate to severe CHF will prevent myocyte cell loss and therefore delay the development of decompensated CHF. The results generated will yield critical insights into the role of skeletal and cardiac muscle apoptosis during acute CHF decompensation. These data have the potential to translate into more effective, clinically relevant CHF treatments.